Project Summary A growing body of literature implicates the brain in the control of glucose homeostasis, yet very little is known with respect to the mechanisms whereby this control occurs. The goal of the proposed work is to identify and characterize the neurocircuits linking key brain regions involved in glycemic control and to determine how they mediate their effects. Recent work from the applicant?s lab demonstrates that photo-activation of hypothalamic ventromedial nucleus (i.e. VMNSF1) neurons is both necessary and sufficient for glucose counterregulation, suggesting that these neurons play a physiological role in glycemic control. Moreover, a subset of VMNSF1 neurons that project to the anterior bed nucleus of the stria terminalis (aBNST) are implicated in this glucoregulatory circuit. In addition, our preliminary data demonstrates that photo-activation of a subset of VMN neurons expressing nitric oxide synthase-1 (NOS1) mimics the effect of VMNSF1 to acutely raise blood glucose, and that this appears to involve projections to the aBNST. In Specific Aim 1, we propose to determine if activation of VMNNOS1 neurons is required for intact counter-regulatory responses to hypoglycemia. In Specific Aim 2, we propose to identify and characterize the subset of aBNST neurons involved in glucose counterregulation that lies downstream of VMN neurons. To accomplish these objectives, we will employ optogenetics and DREADD technologies in combination with viral, mouse genetics, and immunohistochemical techniques. Overall, this work has the potential to fundamentally advance our understanding of neurocircuits that regulate glucose metabolism and determine whether dysregulation of these circuits contributes to the pathogenesis of diabetes.